Next frontier to fight superbugs " disarming germs by busting up their gangs

Monday

Dec 31, 2007 at 10:30 PM

WASHINGTON — Think of germs as gangsters. One thug lurking on a corner you might outrun, but a dozen swaggering down the street? Yikes.

LAURAN NEERGAARD

WASHINGTON — Think of germs as gangsters. One thug lurking on a corner you might outrun, but a dozen swaggering down the street? Yikes.

Bacteria make their own gangs, clustering quietly in the body until there's a large enough group to begin an attack. This is the next frontier in fighting drug-resistant superbugs.

The idea: Don't just try to kill bacteria. The bugs will always find a way to thwart the next antibiotic.

The new goal is to disable bacteria's ability to sicken, so scientists can throw superbugs a one-two punch. And attempts to bust up germ gangs are leading the race to create these novel anti-infectives — using everything from compounds in Pinot Noir to some popular bone-building drugs.

"It's a stealth approach," says chemist Kim Janda of the Scripps Research Institute, who is developing a vaccine against notorious drug-resistant staph that prevents the bacteria from ganging up.

"We're trying to find the Achilles heel in drug-resistant bacteria," adds Matthew Redinbo of the University of North Carolina, Chapel Hill — who did find one.

Redinbo's team discovered that certain osteoporosis drugs blocked one E. coli germ from spreading antibiotic-resistance genes to another. Interrupting this recruitment of new gangsters confused the drug-resistant bugs enough that they committed suicide, leaving only easy-to-treat germs behind.

All of this research is in very early stages. But Dr. Julie Gerberding, chief of the Centers for Disease Control and Prevention, calls disarming bacteria a long-needed new approach.

It is "like lasers going in to destroy certain parts of the bacteria as opposed to a bomb that blows the whole thing up," Gerberding told Congress recently. These "next-generation strategies are not proven yet, but really something that needs a lot more attention and focus."

Indeed, despite a rise in bacteria that withstand today's best treatments, there are few novel antibiotics under development — and germs have evolved such complex ways to survive antibiotics' frontal assault that new ones eventually will wear out, too.

Hence the quest to disarm germs. Scientists are trying to disable "virulence factors," molecules that help germs worm their way into the body, or block germ-emitted toxins.

But much of the new research centers on simply keeping germs from clustering.

"We're finding new ways to prevent disease without killing the microbial agent ... rather, neutralizing it somehow," says University of Rochester dentist Hyun Koo, who is using compounds left over from vineyards' wine-making to bust up gooey bacteria masses known as biofilms.

Adds Scripps' Janda: "If you break them up, they don't have that strength in number. They're not going to do like a gang and beat people up."

Among the methods under study:

—Germs talk to each other, by sending out radar-like chemical signals that sense when enough of their mates are lurking for them to switch on and sicken. Scientists call this "quorum sensing." Jam their frequencies, and the germs won't know when they've got a quorum — they'll just hang around harmlessly until the immune system picks them off.

Janda's team designed a molecule that triggers the immune system to form bloodhound-like antibodies that gobble up the communication chemicals sent by deadly staph aureus bacteria. Janda injected some mice with those antibodies and others with a dummy drug. Then he gave all the mice a lethal dose of staph. The antibody-protected mice never got sick, while their unprotected neighbors died within a day.

—Other times germs need only to rub shoulders with a neighbor to start doing damage. Antibiotic-resistant E. coli snuggles up to a still treatable germ and shoots the newcomer with DNA that will turn it drug-resistant, too.

At UNC, Redinbo's team found the enzyme that sparks that whole process could be blocked by bone-building osteoporosis drugs already on the market, including one called etidronate. When they added just a bone drug, not antibiotics, to the drinking water of E. coli-infected mice, the rodents' bacteria levels plummeted. Why? The resistant germs not only couldn't spread their bad genes, they wound up committing suicide.

"This was a huge surprise," says Redinbo, who now is testing if the approach will work on other bacteria — and is checking his hospital's records to see if women taking osteoporosis drugs just might be less vulnerable to hospital-spread infections.

—Then there are biofilms, where germs literally glue themselves together under a crusty shell difficult for antibiotics to penetrate. Rochester's Koo aims to break up cavity-causing dental plaque, the best known biofilm, with compounds called polyphenols culled from fermented grape skins.

A type of strep bacteria forms dental plaque, by secreting enzymes called GTFs that in turn produces the biofilm's glue. When Koo added polyphenols to lab dishes teeming with strep, GTF production plummeted 85 percent. The germs couldn't get sticky enough. For the record, extracts from Cabernet Franc and Pinot Noir worked best.

The approach should work against strep strains that cause pneumonia, too, Koo says. His ultimate goal is a cavity-preventing rinse, but much more research is required — and Koo warns not to swish with wine in the meantime. It's too acidic.

"You'll wind up with stained teeth and also erosion from the acidity," he cautions.

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